Synthesis and Characterization of Novel “3 + 2” Oxorhenium Complexes, ReO[SNO][NN]

The present paper deals with the synthesis and structural characterization of novel neutral oxorhenium(V) complexes of the general formula ReO[SNO][NN]. The simultaneous action of the tridentate SNO ligand, N-(2-mercaptoacetyl)glycine (1), and the bidentate NN ligand, N-phenylpyridine-2-aldimine (2), on ReOCl3(PPh3)2 leads to the formation of two isomers 4a and 4b of the general formula ReO[SNO][NN], as a result of the different orientations of the NN ligand. In both cases, the SNO donor atoms of the tridentate ligand occupy the three positions in the equatorial plane of the distorted octahedron, whereas the oxo group is always directed toward one of the apical positions. In the first isomer, 4a, the imino nitrogen of the NN ligand occupies the fourth equatorial position and the pyridine type nitrogen is directed trans to the oxo group, while in the second isomer, 4b, the imino nitrogen of the NN ligand occupies the apical position trans to the oxo group and the pyridine type nitrogen completes the equatorial plane of the distorted octahedron. The [SNO][NN] mixed-ligand system was applied in the synthesis of the oxorhenium complex 5 in which the 1-(2-methoxyphenyl)piperazine moiety, a fragment of the true 5-HT1A antagonist WAY 100635, has been incorporated in the NN bidentate ligand (NN is N-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}pyridine-2-aldimine). In this case, high-performance liquid chromatography and NMR showed the existence of one isomer, 5, in which the pyridine nitrogen is trans to the oxo core, as demonstrated by crystal structure analysis

Oxorhenium Phosphinophenolato Complexes with Model Peptide Fragments: Synthesis, Characterization, and Stability Considerations

The synthesis and characterization of a series of mixed-ligand oxorhenium(V) complexes containing the o-diphenylphosphinophenolato ligand (HL) and model peptide fragments acting as the tridentate coligand are reported. Thus, by reacting equimolar amounts of tiopronin, Gly-Gly, Gly-l-Phe, or glutathione (GSH) peptides on the [(n-C4H9)4N][ReOCl3(L)] precursor in refluxing MeCN/MeOH or aqueous MeCN/MeOH mixtures, the following complexes were obtained:  ReO{[SC(CH3)CONCH2COO][L]}[(n-C4H9)4N], 1, ReO{[H2NCH2CONCH2COO][L]}, 2, ReO{[H2NCH2CONCH(CH2C6H5)COO][L]}, 3, and ReO{[SCH2CH(NHCOCH2CH2CHNH2COOH)CONCH2COO][L]}Na, 4. The compounds are closed-shell 18-electron oxorhenium species adopting a distorted octahedral geometry, as demonstrated by classical spectroscopical methods including multinuclear NMR. X-ray diffraction analyses for 1 and 2 are also reported. By comparative stability studies of complexes 1−3 against excess GSH it was shown that complex 3 containing the bulky C6H5CH2 substituent adjacent to the coordinated carboxylate group of Phe is the most stable complex

Synthesis and Characterization of Six-Coordinate “3 + 2” Mixed-Ligand Oxorhenium Complexes with the <i>o</i>-Diphenylphosphinophenolato Ligand and Tridentate Coligands of Different N and S Donor Atom Combinations

A series of octahedral six-coordinate oxorhenium(V) mixed ligand complexes containing the common [ReO(L)]2+ fragment (L = o-OC6H4P(C6H5)2] have been synthesized and characterized. Hence, it was shown that the [ReO(L)]2+ moiety can accommodate a variety of tridentate ligands containing a central amine group amenable to deprotonation and different combinations of lateral groups, such as ethylamine, substituted ethylamine, ethylthiol, and ethylthioether arms. In particular, by reaction of equimolar amounts of the pertinent HLn ligands with the [(n-C4H9)4N][ReOCl3(L)] precursor in refluxing acetonitrile/methanol or dichloromethane/methanol mixtures, the following series of [ReO(Ln)(L)]+/0 oxorhenium(V) complexes has been generated:  ReO{[N(CH2CH2NH2)2][o-OC6H4P(C6H5)2]}Cl (1); ReO{[(C2H5)2NCH2CH2NCH2CH2S][o-OC6H4P(C6H5)2]} (2); ReO{[(CH2)4NCH2CH2NCH2CH2S][o-OC6H4P(C6H5)2]} (3); and ReO{[C2H5SCH2CH2NCH2CH2S][o-OC6H4P(C6H5)2]} (4). The complexes are closed-shell 18-electron oxorhenium species, which adopt octahedral geometries both in solution and in the solid state, as established by conventional physicochemical techniques including multinuclear NMR and single-crystal X-ray diffraction analyses

Oxorhenium Phosphinophenolato Complexes with Model Peptide Fragments: Synthesis, Characterization, and Stability Considerations

The synthesis and characterization of a series of mixed-ligand oxorhenium(V) complexes containing the o-diphenylphosphinophenolato ligand (HL) and model peptide fragments acting as the tridentate coligand are reported. Thus, by reacting equimolar amounts of tiopronin, Gly-Gly, Gly-l-Phe, or glutathione (GSH) peptides on the [(n-C4H9)4N][ReOCl3(L)] precursor in refluxing MeCN/MeOH or aqueous MeCN/MeOH mixtures, the following complexes were obtained:  ReO{[SC(CH3)CONCH2COO][L]}[(n-C4H9)4N], 1, ReO{[H2NCH2CONCH2COO][L]}, 2, ReO{[H2NCH2CONCH(CH2C6H5)COO][L]}, 3, and ReO{[SCH2CH(NHCOCH2CH2CHNH2COOH)CONCH2COO][L]}Na, 4. The compounds are closed-shell 18-electron oxorhenium species adopting a distorted octahedral geometry, as demonstrated by classical spectroscopical methods including multinuclear NMR. X-ray diffraction analyses for 1 and 2 are also reported. By comparative stability studies of complexes 1−3 against excess GSH it was shown that complex 3 containing the bulky C6H5CH2 substituent adjacent to the coordinated carboxylate group of Phe is the most stable complex

Novel Six-Coordinate Oxorhenium “3 + 2” Mixed-Ligand Complexes Carrying the SNS/PO Donor Atom Set: Synthesis and Characterization

Replacing the monothiolate group of the so-called “3 + 1” mixed-ligand oxorhenium(V) complexes with the bidentate phosphinophenolate ligand produces novel “3 + 2” mixed-ligand complexes carrying the SNS/PO donor atom set. Thus, reactions of either [ReOCl3(L)]- or [ReOCl2(L)(PPh3)] (HL = o-HOC6H4P(C6H5)2) with aminedithiol (H2Ln) in dichloromethane methanol solutions lead to six-coordinate mixed-ligand oxo−Re(V) complexes of the type [ReO(Ln)(L)], where H2L1 = CH3CH2N(CH2CH2SH)2 (1), H2L2 = (CH3CH2)2NCH2CH2N(CH2CH2SH)2 (2), and H2L3 = CH3CH2SCH2CH2N(CH2CH2SH)2 (3). The coordination geometry around rhenium is distorted octahedral with the SNS donors of the aminedithiolate and the phosphorus of the phosphinophenolate ligand defining the equatorial plane, while the apical positions are occupied by the oxo group and the oxygen atom of the HL ligand, as shown by single-crystal X-ray analyses of 1 and 3. The strong metal−phosphorus bonds together with the chelating properties of both ligands contribute to the stability of 18-electron [ReO(Ln)(L)] complexes. In fact, these six-coordinate species appear to be much more substitution inert than the “3 + 1” analogous complexes vs excess thiolate, such as cysteine or glutathione, during appropriate challenge reactions

Synthesis and Characterization of Six-Coordinate “3 + 2” Mixed-Ligand Oxorhenium Complexes with the <i>o</i>-Diphenylphosphinophenolato Ligand and Tridentate Coligands of Different N and S Donor Atom Combinations

A series of octahedral six-coordinate oxorhenium(V) mixed ligand complexes containing the common [ReO(L)]2+ fragment (L = o-OC6H4P(C6H5)2] have been synthesized and characterized. Hence, it was shown that the [ReO(L)]2+ moiety can accommodate a variety of tridentate ligands containing a central amine group amenable to deprotonation and different combinations of lateral groups, such as ethylamine, substituted ethylamine, ethylthiol, and ethylthioether arms. In particular, by reaction of equimolar amounts of the pertinent HLn ligands with the [(n-C4H9)4N][ReOCl3(L)] precursor in refluxing acetonitrile/methanol or dichloromethane/methanol mixtures, the following series of [ReO(Ln)(L)]+/0 oxorhenium(V) complexes has been generated:  ReO{[N(CH2CH2NH2)2][o-OC6H4P(C6H5)2]}Cl (1); ReO{[(C2H5)2NCH2CH2NCH2CH2S][o-OC6H4P(C6H5)2]} (2); ReO{[(CH2)4NCH2CH2NCH2CH2S][o-OC6H4P(C6H5)2]} (3); and ReO{[C2H5SCH2CH2NCH2CH2S][o-OC6H4P(C6H5)2]} (4). The complexes are closed-shell 18-electron oxorhenium species, which adopt octahedral geometries both in solution and in the solid state, as established by conventional physicochemical techniques including multinuclear NMR and single-crystal X-ray diffraction analyses

Glutathione-Mediated Metabolism of Technetium-99m SNS/S Mixed Ligand Complexes: A Proposed Mechanism of Brain Retention

Two series of [99mTc](SNS/S) mixed ligand complexes each carrying the N-diethylaminoethyl or the N-ethyl-substituted bis(2-mercaptoethyl)amine ligand (SNS) are produced at tracer level using tin chloride as reductant and glucoheptonate as transfer ligand. The identity of [99mTc](SNS/S) complexes is established by high-performance liquid chromatographic (HPLC) comparison with authentic rhenium samples. The para substituent R on the phenylthiolate coligand (S) ranges from electron-donating (−NH2) to electron-withdrawing (−NO2) groups, to study complex stability against nucleophiles as a result of N- and R-substitution. The relative resistance of [99mTc](SNS/S) complexes against nucleophilic attack of glutathione (GSH), a native nucleophilic thiol of 2 mM intracerebral concentration, is investigated in vitro by HPLC. The reaction of [99mTc](SNS/S) complexes with GSH is reversible and advances via substitution of the monothiolate ligand by GS- and concomitant formation of the hydrophilic [99mTc](SNS/GS) daughter compound. The N-diethylaminoethyl complexes are found to be more reactive against GSH as compared to the N-ethyl ones. Complex reactivity as a result of R-substitution follows the sequence −NO2 ≫ −H > −NH2. These in vitro findings correlate well with in vivo distribution data in mice. Thus, brain retention parallels complex susceptibility to GSH attack. Furthermore, isolation of the hydrophilic [99mTc](SNS/GS) metabolite from biological fluids and brain homogenates provides additional evidence that the brain retention mechanism of [99mTc](SNS/S) complexes is GSH-mediated

Novel Six-Coordinate Oxorhenium “3 + 2” Mixed-Ligand Complexes Carrying the SNS/PO Donor Atom Set: Synthesis and Characterization

Replacing the monothiolate group of the so-called “3 + 1” mixed-ligand oxorhenium(V) complexes with the bidentate phosphinophenolate ligand produces novel “3 + 2” mixed-ligand complexes carrying the SNS/PO donor atom set. Thus, reactions of either [ReOCl3(L)]- or [ReOCl2(L)(PPh3)] (HL = o-HOC6H4P(C6H5)2) with aminedithiol (H2Ln) in dichloromethane methanol solutions lead to six-coordinate mixed-ligand oxo−Re(V) complexes of the type [ReO(Ln)(L)], where H2L1 = CH3CH2N(CH2CH2SH)2 (1), H2L2 = (CH3CH2)2NCH2CH2N(CH2CH2SH)2 (2), and H2L3 = CH3CH2SCH2CH2N(CH2CH2SH)2 (3). The coordination geometry around rhenium is distorted octahedral with the SNS donors of the aminedithiolate and the phosphorus of the phosphinophenolate ligand defining the equatorial plane, while the apical positions are occupied by the oxo group and the oxygen atom of the HL ligand, as shown by single-crystal X-ray analyses of 1 and 3. The strong metal−phosphorus bonds together with the chelating properties of both ligands contribute to the stability of 18-electron [ReO(Ln)(L)] complexes. In fact, these six-coordinate species appear to be much more substitution inert than the “3 + 1” analogous complexes vs excess thiolate, such as cysteine or glutathione, during appropriate challenge reactions

New Oxorhenium(V) Complexes from the Widely Used Diaminedithiol (DADT) Ligand System

Synthesis of the 2,9-dimethyl-4,7-diaza-4-alkyl-2,9-decanedithiol (1, alkyl = morpholinylethyl in a, and alkyl = pyrrolidinylethyl in b), following a widely used synthetic scheme for diaminedithiol (DADT) ligands, led to the isolation of 1-alkyl-2-(1‘-methyl-1‘-sulfanylethyl)-3-(2‘ ‘-methyl-2‘ ‘-sulfanylpropyl)diazolidine (3) as the major product. Both ligands 1 and 2 gave complexes with the oxorhenium ReO(V) core. Ligand 1 gave the expected ReO[SNNS] complex (2) with the side chain on nitrogen in the syn configuration. Ligand 3 gave, in the presence of a monodentate aromatic thiol, complexes of the ReO[SNN][S][S] (4) and ReO[SNN][S] type (5), respectively, in which the diazolidine ring has rearranged to a thiazolidine ring. Crystallographic analysis showed that in 4 the coordination geometry about the metal is distorted octahedral where the equatorial plane is defined by the sulfur and one of the nitrogen atoms of the ligand and the two sulfurs of the aromatic thiols, while the axial positions are occupied by the oxygen of the ReO core and the second nitrogen of the ligand. Specifically, complex 4a crystallizes in space group P21/c, a = 15.63(1) Å, b = 15.28(2) Å, c = 16.07(1) Å, β = 113.78(2)°, V = 3512(5) Å3, Z = 4. Complex 4b crystallizes in space group P21/n, a = 14.560(9) Å, b = 14.804(9) Å, c = 19.85(1) Å, β = 90.94(2)°, V = 4278(1) Å3, Z = 4. In 5b, the coordination geometry is distorted square pyramidal with the SNN donor atom of the ligand and the aromatic thiol defining the equatorial plane and the doubly bonded oxygen occupying the apex of the pyramid. Complex 5b crystallizes in space group P1̄, a = 9.387(5) Å, b = 11.306(5) Å, c = 14.040(6) Å, α = 84.51(1)°, β = 84.45(2)°, γ = 87.17(1)°, V = 1475(1) Å3, Z = 2. All isolated complexes are neutral and lipophilic. Complete assignments of 1H and 13C NMR resonances are reported

Synthesis and Characterization of Novel Oxotechnetium (⁹⁹Tc and ^99mTc) and Oxorhenium Complexes from the 2,2‘-Bipyridine (NN)/Thiol (S) Mixed-Ligand System

The synthesis and characterization of oxotechnetium and oxorhenium mixed-ligand complexes of the general formula MO[NN][S]3 (M = 99Tc and Re), where NN represents the bidentate ligand 2,2‘-bipyridine and S represents a monodentate thiophenol, is reported. The complexes were prepared by ligand exchange reactions using 99Tc-gluconate and ReOCl3(PPh3)2 as precursors for the oxotechnetium and oxorhenium complexes, respectively. Compound 1 (M = 99Tc, S = 4-methylthiophenol) crystallizes in the monoclinic space group P21/a, a = 23.12(1) Å, b = 14.349(6) Å, c = 8.801(4) Å, β = 94.81(2)°, V = 2918(2) Å3, Z = 4. Compound 3 (M = Re, S = 4-methylthiophenol) crystallizes in the monoclinic space group P21/a, a = 23.018(9) Å, b = 14.421(5) Å, c = 8.775(3) Å, β = 94.78(1)°, V = 2903(2) Å3, Z = 4. Compound 4 (M = Re, S = 4-methoxythiophenol) crystallizes in the orthorhombic space group Pbca, a = 16.32(1) Å, b = 24.55(2) Å, c = 16.94(1) Å, V = 6788(9) Å3, Z = 8. In all cases, the coordination geometry around the metal is distorted octahedral with the equatorial plane being defined by the three sulfur atoms of the thiophenols and one nitrogen atom of 2,2‘-bipyridine, while the apical positions are occupied by the second nitrogen atom of 2,2‘-bipyridine and the oxygen of the MO core. The complexes are stable, neutral, and lipophilic. Complete 1H and 13C NMR assignments are reported for all complexes. The analogous oxotechnetium complexes have been also synthesized at tracer level (99mTc) by mixing the 2,2‘-bipyridine and the corresponding thiol with Na99mTcO4 generator eluate using NaBH4 as reducing agent. Their structure was established by chromatographic comparison with authentic oxotechnetium and oxorhenium complexes using high performance liquid chromatography techniques